The present invention relates to a method for preparing 2-phenyl-3-aminopyridine, its substituted phenyl derivatives, and salts thereof. 2-phenyl-3-aminopyridine and its substituted derivatives are useful in the preparation of compounds that have utility as substance P antagonists.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, members of which exert prompt stimulatory action on smooth muscle tissue. Substance P is a pharmaceutically active neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence that is described in U.S. Pat. No. 4,680,283. The involvement of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For example, substance P has been shown to be involved in the transmission of pain or migraine, as well as in central nervous system disorders such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, and in gastrointestinal disorders such as ulcerative colitis, irritable bowel syndrome, and Crohn's disease. Tachykinin antagonists have been reported as useful in treating these conditions and in treating cardiovascular diseases, allergic conditions, immunoregulation, vasodilation, bronchospasm, reflex or neuronal control of the viscera, senile dementia of the Alzheimer type, emesis, sunburn, and Helicobacter pylori infection.
A variety of substance P antagonists can be prepared from 2-phenyl-3-aminopyridine. For example, U.S. Pat. No. 5,323,929 describes substance P antagonists of the formula ##STR1##
where R.sup.3 is a substituted, or unsubstituted aryl, heteroaryl, or cycloalkyl group. These antagonists can be prepared by reduction of 2-phenyl-3-aminopyridine, followed by reductive amination of the resulting 2-phenyl-3-aminopiperidine using an appropriate aldehyde of the formula R.sup.3 CHO. Alternately, these substance P antagonists can be obtained by reacting 2-phenyl-3-aminopyridine with a compound of the formula R.sup.3 CHO or R.sup.3 CH.sub.2 X, where X is a leaving group, to produce the pyridine analog of the substance P antagonist. The pyridine analog is then reduced to obtain the final product.
Additional substance P antagonists that can be prepared from 2-phenyl-3-aminopyridine are described in U.S. Pat. No. 5,773,450, and in WO 97/08144 and PCT/IB97/01466. Methods employing 2-phenyl-3-aminopyridine to make substance P antagonists are also described in U.S. Pat. No. 5,232,929.
However, the conventional method employed to prepare 2-phenyl-3-aminopyridine, described by Miller and Farrell (Tetrahedron Letters, 1998, 39: 6441-6444) is air sensitive and results in a relatively low yield.